Disorders of colonic motility are thought to underlie several common clinical problems, yet of all segments of the human gut, motility of the large bowel is least understood. Whereas definitions of normal motility in the esophagus, stomach, and small bowel have allowed regional pathophysiologies to be recognized, normal patterns of motility in the colon are highly variable and poorly defined. Thus, even though several distinctive colonic motor patterns have been described in disease, their relationships with symptoms are unclear.
Measurement of colonic transit is a useful clinical and research technique to evaluate patients with suspected motility disorders of the colon. There are several methods by which colonic transit can be quantified in humans. These approaches include (1) techniques that assess mouth to anus transit, which, however, provide no information on segmental colonic transit; (2) cinefluorography, which is helpful but severely limited by the level of radiation required; (3) the ingestion of radiopaque markers of different shapes with a single or sequential abdominal radiographs; (4) radioisotopic methods, by which liquid radiolabels have been infused into the cecum or splenic fixture. Other radioisotopic methods that have been used include radiolabeled solid markers administered orally either as free particles or enclosed within a capsule. For example, .sup.131 I-labeled cellulose fiber has been used in radioscintigraphic studies of gastric and small bowel transit. See, for example, M. Camilleri et al., Am. J. Physiol., 257, G284 (1989). However, this material is difficult to synthesize, employs a .beta.-radiation source and may be thermally altered when the food carrier is cooked.
These radiological and radioisotopic methods have provided quantitative data on regional colon transit. However, none of these methods are ideal for physiological studies for a number of reasons: some involve intubation and/or preparation of the colon; some evaluate liquid transit in the colon, whereas the movement of particulate matter is probably more relevant. Others do not identify the precise starting point from which colonic transit can be assessed. In particular, the radiopaque marker method, although widely available, inexpensive, and reproducible, requires that the patient is available for four or, more commonly, seven days in order to evaluate the transit profile in the colon by means of two radiographs. Metcalf et al., Gastroenterology, 92:40 (1987); Stivland et al., Gastroenterology, 101:107 (1991).
The need to have a test with a faster completion time led us to develop a radioscintigraphic approach that has since been simplified and utilized clinically. Proano et al., Am. J. Physiol., 258:G856 (1990).; Camilleri et al., Gastroenterology, 103:3 (1992); Charles et al., Mayo Clin. Proc., 70:113 (1995). The method involves radiolabeling ion exchange resin pellets with radioisotopes such as .sup.99 Tc or .sup.111 In and delivering them to the colon in a delayed-release, polymer-coated capsule that dissolves in the alkaline pH of the terminal ileum. However, although initial research studies have shown that these radiolabeled resin pellets are efficacious in measuring colonic transit, there are several constraints on their widespread use.
Specifically, since the resin pellets are not listed in the United States Pharmacopoeia (USP) and are considered to be a new drug moiety, an investigational new drug (IND) application must be filed with the Federal Drug Administration (FDA) prior to their use. In a clinical venue, the IND application and the accompanying requirement of notification of every new project and adverse effect is burdensome and expensive and reduces considerably the cost efficacy of the study. Moreover, and also as a result of the fact that the resin pellets are classified as an investigational drug, there are problems with reimbursement from third-party payers for the clinical use of colonic transit tests.
Therefore, an improved marker for the measurement of colonic transit that overcomes all of the aforementioned drawbacks is needed as such a marker would be extremely useful for diagnostic and physiological studies in health and disease.